Neutrophils, eosinophils and basophils are known as granulocytes because of their content of cytoplasmic granules, or phagocytes because they may phagocytize or ingest bacteria, microorganisms and other types of foreign materials. These cells are produced from common progenitor cells in the bone marrow of a human or animal, and are known to circulate in peripheral blood and enter tissues as necessary for control of infection or to participate in any type of inflammatory reaction. The neutrophil is the most common leukocyte in human and animal peripheral blood.
In the response to any type of infection or inflammation, granulocytes are activated to migrate to the appropriate area in response to chemoattractant factors, such as, certain bacterial products, complement component, and other factors. This attraction process is termed chemotaxis. Once in an area of inflammation or infection, granulocytes and mononuclear phagocytes must establish a firm attachment to their targets. For this purpose, these cells possess a number of specific cell surface receptor glycoproteins that promote this interaction, such as complement, Fc, and fibronectin receptors.
One family of cell surface receptor glycoproteins is the leukocyte cell adhesion molecular (LEU-CAM) family (CD11/CD18). This family is comprised of cell surface proteins which have multiple subunits. The members of this family include LFA-1 (CD 11a/CD18), Mol (CD 11b/CD18), and P150,94 (CD 11c/CD18).
Activation of granulocytes (and particularly neutrophils) is involved in numerous disorders and diseases, particularly those involving inflammation. While the inflammatory response of granulocytes is vital to the eradication of invading microorganisms, substantial evidence indicates that inflammatory phagocytes cause damage to various organs and tissues when these cells are activated as part of an ongoing (chronic) process, or are triggered in an unregulated manner. The adhesion and spreading of activated granulocytes (e.g., neutrophils) to vascular endothelial cells with the subsequent release of toxic oxidative metabolites and proteases has been implicated in the organ damage observed in diseases or disorders (“granulocyte-mediated disorders”) such as adult respiratory distress syndrome (ARDS; shock lung syndrome), glomerulonephritis, and inflammatory injury occurring after reperfusion of ischemic tissue such as to the heart, bowel, and central nervous system, among others. Heart muscle or myocardium may be particularly vulnerable to the inflammatory response of activated granulocytes. For example, it has been suggested that inhibition of the activation of granulocytes prior to cardiac insult (e.g., myocardial ischemia) may result in significantly smaller damage, and reduced myocardial infarct size.
U.S. Pat. No. 4,840,793 to Todd III, et al., as well as related U.S. Pat. No. 4,935,234, U.S. Pat. No. 5,049,659 and U.S. Pat. No. 5,019,648 describe the inhibition of activated granulocytes by administering monoclonal antibodies that inhibit adhesion-dependent functions of glycoproteins such as CD11b to inhibit migration of neutrophils to an area of inflammation or infection. Other groups have used recombinant soluble adhesive receptors as anti-inflammatory compounds. Thus, the majority of treatments for granulocyte-mediated disorders or diseases have been treated by systemically applying exogenous substances that interact with granulocytes that have already undergone activation. It would be highly desirable to more directly inhibit granulocyte activation, as described herein.